This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Oseltamivir (tamiflu) [1] is currently the main antiviral drug for treatment of H1N1pdm, more commonly known as "swine flu" (http://www.ks.uiuc.edu/Research/swineflu/). The drug functions by competitively inhibiting neuraminidase (specifically N1 subtype), a flu specific glycoprotein that is responsible for mediating the release of newly synthesized virions [2]. In effect, oseltamivir stems viral infection by preventing the virus from leaving an infected cell. Of great concern however, is the emergence of point mutation induced drug resistance to oseltamivir for H1N1pdm strains already reported in North America and Europe [3, 4, 5]. In order to develop new and effective therapies, it is therefore critical to understand both the specific interactions responsible for binding oseltamivir with influenza N1 subtype neuraminidases and the mechanisms responsible for mutation-induced drug resistance.